Modeling and simulation as a tool to assess voriconazole exposure in the central nervous system
Autor(a) principal: | |
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Data de Publicação: | 2023 |
Outros Autores: | , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFRGS |
Texto Completo: | http://hdl.handle.net/10183/281030 |
Resumo: | Voriconazole is a triazole antifungal used empirically for the treatment of complicated meningitis associated with Cryptococcus neoformans. Biopsy studies show that the drug exhibits adequate brain penetration although levels of cerebral spinal fluid (CSF) are highly variable. Considering that CSF is one of the main surrogates for CNS exposure, the present work proposed the building of a population pharmacokinetic modeling (popPK) model able to describing the exposure achieved by voriconazole in the plasma, interstitial cerebral fluid and CSF of healthy and infected rats. The developed popPK model was described by four compartments, including total plasma, free brain and total CSF concentrations. The following PK parameters were determined: Km = 4.76 mg/L, Vmax = 1.06 mg/h, Q1 = 2.69 L, Qin = 0.81 h1 and Qout = 0.63 h1. Infection was a covariate in the Michaelis–Menten constant (Km) and intercompartmental clearance from the brain tissue compartment to central compartment (Qout). Simulations performed with the popPK model to determine the probability of reaching the therapeutic target of fAUC > MIC showed that VRC has sufficient tissue exposure in the interstitial fluid and in the CSF for the treatment of fungal infections in these tissues at prevalent minimum inhibitory concentrations. |
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Staudt, Keli JaquelineDias, Bruna BernarAlves, Izabel AlmeidaLelièvre, BénédicteBouchara, Jean-PhilippeAraújo, Bibiana Verlindo de2024-11-09T06:40:17Z20231999-4923http://hdl.handle.net/10183/281030001207256Voriconazole is a triazole antifungal used empirically for the treatment of complicated meningitis associated with Cryptococcus neoformans. Biopsy studies show that the drug exhibits adequate brain penetration although levels of cerebral spinal fluid (CSF) are highly variable. Considering that CSF is one of the main surrogates for CNS exposure, the present work proposed the building of a population pharmacokinetic modeling (popPK) model able to describing the exposure achieved by voriconazole in the plasma, interstitial cerebral fluid and CSF of healthy and infected rats. The developed popPK model was described by four compartments, including total plasma, free brain and total CSF concentrations. The following PK parameters were determined: Km = 4.76 mg/L, Vmax = 1.06 mg/h, Q1 = 2.69 L, Qin = 0.81 h1 and Qout = 0.63 h1. Infection was a covariate in the Michaelis–Menten constant (Km) and intercompartmental clearance from the brain tissue compartment to central compartment (Qout). Simulations performed with the popPK model to determine the probability of reaching the therapeutic target of fAUC > MIC showed that VRC has sufficient tissue exposure in the interstitial fluid and in the CSF for the treatment of fungal infections in these tissues at prevalent minimum inhibitory concentrations.application/pdfengPharmaceutics. Basel. Vol. 15, n. 7 (2023), 1781, 13 p.CriptococoseLíquido cefalorraquidianoVoriconazolMeningiteCryptococcosisCerebrospinal fluidVoriconazoleMeningitisBrain microdialysisInterstitial space fluidModeling and simulation as a tool to assess voriconazole exposure in the central nervous systemEstrangeiroinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFRGSinstname:Universidade Federal do Rio Grande do Sul (UFRGS)instacron:UFRGSTEXT001207256.pdf.txt001207256.pdf.txtExtracted Texttext/plain46283http://www.lume.ufrgs.br/bitstream/10183/281030/2/001207256.pdf.txtb997140779f462130f81f73ed8a9be12MD52ORIGINAL001207256.pdfTexto completo (inglês)application/pdf2925075http://www.lume.ufrgs.br/bitstream/10183/281030/1/001207256.pdf81e558b5e5604d1f648733719a1c41bbMD5110183/2810302024-11-10 07:52:42.977124oai:www.lume.ufrgs.br:10183/281030Repositório InstitucionalPUBhttps://lume.ufrgs.br/oai/requestlume@ufrgs.bropendoar:2024-11-10T09:52:42Repositório Institucional da UFRGS - Universidade Federal do Rio Grande do Sul (UFRGS)false |
dc.title.pt_BR.fl_str_mv |
Modeling and simulation as a tool to assess voriconazole exposure in the central nervous system |
title |
Modeling and simulation as a tool to assess voriconazole exposure in the central nervous system |
spellingShingle |
Modeling and simulation as a tool to assess voriconazole exposure in the central nervous system Staudt, Keli Jaqueline Criptococose Líquido cefalorraquidiano Voriconazol Meningite Cryptococcosis Cerebrospinal fluid Voriconazole Meningitis Brain microdialysis Interstitial space fluid |
title_short |
Modeling and simulation as a tool to assess voriconazole exposure in the central nervous system |
title_full |
Modeling and simulation as a tool to assess voriconazole exposure in the central nervous system |
title_fullStr |
Modeling and simulation as a tool to assess voriconazole exposure in the central nervous system |
title_full_unstemmed |
Modeling and simulation as a tool to assess voriconazole exposure in the central nervous system |
title_sort |
Modeling and simulation as a tool to assess voriconazole exposure in the central nervous system |
author |
Staudt, Keli Jaqueline |
author_facet |
Staudt, Keli Jaqueline Dias, Bruna Bernar Alves, Izabel Almeida Lelièvre, Bénédicte Bouchara, Jean-Philippe Araújo, Bibiana Verlindo de |
author_role |
author |
author2 |
Dias, Bruna Bernar Alves, Izabel Almeida Lelièvre, Bénédicte Bouchara, Jean-Philippe Araújo, Bibiana Verlindo de |
author2_role |
author author author author author |
dc.contributor.author.fl_str_mv |
Staudt, Keli Jaqueline Dias, Bruna Bernar Alves, Izabel Almeida Lelièvre, Bénédicte Bouchara, Jean-Philippe Araújo, Bibiana Verlindo de |
dc.subject.por.fl_str_mv |
Criptococose Líquido cefalorraquidiano Voriconazol Meningite |
topic |
Criptococose Líquido cefalorraquidiano Voriconazol Meningite Cryptococcosis Cerebrospinal fluid Voriconazole Meningitis Brain microdialysis Interstitial space fluid |
dc.subject.eng.fl_str_mv |
Cryptococcosis Cerebrospinal fluid Voriconazole Meningitis Brain microdialysis Interstitial space fluid |
description |
Voriconazole is a triazole antifungal used empirically for the treatment of complicated meningitis associated with Cryptococcus neoformans. Biopsy studies show that the drug exhibits adequate brain penetration although levels of cerebral spinal fluid (CSF) are highly variable. Considering that CSF is one of the main surrogates for CNS exposure, the present work proposed the building of a population pharmacokinetic modeling (popPK) model able to describing the exposure achieved by voriconazole in the plasma, interstitial cerebral fluid and CSF of healthy and infected rats. The developed popPK model was described by four compartments, including total plasma, free brain and total CSF concentrations. The following PK parameters were determined: Km = 4.76 mg/L, Vmax = 1.06 mg/h, Q1 = 2.69 L, Qin = 0.81 h1 and Qout = 0.63 h1. Infection was a covariate in the Michaelis–Menten constant (Km) and intercompartmental clearance from the brain tissue compartment to central compartment (Qout). Simulations performed with the popPK model to determine the probability of reaching the therapeutic target of fAUC > MIC showed that VRC has sufficient tissue exposure in the interstitial fluid and in the CSF for the treatment of fungal infections in these tissues at prevalent minimum inhibitory concentrations. |
publishDate |
2023 |
dc.date.issued.fl_str_mv |
2023 |
dc.date.accessioned.fl_str_mv |
2024-11-09T06:40:17Z |
dc.type.driver.fl_str_mv |
Estrangeiro info:eu-repo/semantics/article |
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http://hdl.handle.net/10183/281030 |
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1999-4923 |
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001207256 |
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http://hdl.handle.net/10183/281030 |
dc.language.iso.fl_str_mv |
eng |
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dc.relation.ispartof.pt_BR.fl_str_mv |
Pharmaceutics. Basel. Vol. 15, n. 7 (2023), 1781, 13 p. |
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info:eu-repo/semantics/openAccess |
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openAccess |
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